QT length during methadone maintenance treatment: gene × dose interaction

El Hadi Zerdazi*, Florence Vorspan, Andries T. Marees, François Naccache, Jean Pierre Lepine, Jean Louis Laplanche, Nathalie Prince, Cynthia Marie-Claire, Frank Bellivier, Stéphane Mouly, Vanessa Bloch

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

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Abstract

Methadone is known to be a risk factor for sudden death by enlarging ECG QT corrected (QTc) interval. For other medical conditions, QTc lengthening has been described as the result of interactions between pharmacological treatments and genetic factors. Former heroin-dependent subjects under methadone maintenance treatment in remission for at last 3 months were recruited. We studied the association between QTc length (Bazett formula) and 126 SNPs located on five genes (KCNE1, KCNQ1, KCNH2, NOS1AP and SCN5A) previously associated with drug-induced QT prolongation. Both SNP-based and gene-based approaches were used, and we tested also the interaction of the top SNP with methadone dosage to predict the QTc length. In our sample of 154 patients, current methadone daily dose was associated with QTc length (r Pearson  = 0.26; P = 10 −3 ). Only one SNP, rs11911509 on KCNE1, remained significantly associated with QT length after correction for multiple testing (P = 3.84 × 10 −4 ; p corrected  = 0.049). Using a gene-based approach, KCNE1 was also significantly associated with QTc length (p empirical  = 0.02). We found a significant interaction between methadone dosage and rs11911509 minor allele count (allele A vs. C; P = 0.01). Stratified analysis revealed that the correlation between QTc length and methadone dosage was restricted only to AA carriers of this top SNP. Patients’ genetic background should be taken into account in the case of clinically relevant QT enlargement during methadone maintenance treatment.

Original languageEnglish
Pages (from-to)96-106
Number of pages11
JournalFundamental and Clinical Pharmacology
Volume33
Issue number1
Early online date7 Aug 2018
DOIs
Publication statusPublished - Feb 2019

Funding

METHADOSE study, OST07013 was funded by the DRC (Direction de la Recherche Clinique) of the Assistance Publique—Hôpitaux de Paris). F.V. was also funded by: the Mission Interministerielle de Lutte contre la Drogue & la Toxicomanie (MILDT)—Institut National de la Sante & la Recherche Medicale (INSERM; grant ASE07082KSA) and by the BioPsy Laboratory of Excellence; this work was therefore supported by French state funds managed by the ANR within the Investissements d’Avenir program under reference ANR-11-IDEX-0004-02.

FundersFunder number
ANR-11-IDEX-0004-02
BioPsy Laboratory of Excellence
Direction de la Recherche Clinique
Institut National de la Sante & la Recherche Medicale
Mission Interministerielle de Lutte contre la Drogue & la Toxicomanie
Diabetes Research Center
Agence Nationale de la Recherche
Institut national de la santé et de la recherche médicaleASE07082KSA
Assistance Publique - Hôpitaux de ParisOST07013

    Keywords

    • KCNE1
    • methadone
    • QT prolongation
    • rs11911509

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